tbuckley/cabot-search huggingface dataset:
Abstract 6420: Harnessing immune responses in prostate MMRd tumors treated with immune checkpoint blockade
Authors: Marcel Arias Badia, Zenghua Fan, Yee May Lwin, PeiXi Chen, Aahir Srinath, Lawrence Fong
Journal: Cancer Research (2023)

Abstract There is increasing evidence correlating tumor mutational burden with response to immunotherapy in many different types of cancer. Some tumors show high microsatellite instability (MSI-H) as a consequence of the loss of function of mismatch repair (MMR) genes, which would resolve DNA damage in normal conditions. MSH2 plays a critical role in MMR, and several studies have identified mutations in MSH2 as key drivers of MSI in tumors. In preclinical mouse models, MMR deficiency and high microsatellite instability have been previously shown to translate into higher sensitivity to anti-PD-1 treatment. Despite the advances led by the recent tumor-agnostic approval of checkpoint inhibitors for highly mutated tumors, response rates among MMR-deficient (MMRd) tumors in humans are variable, and the mechanisms behind such heterogeneity are still poorly understood. We successfully knocked out the MSH2 gene in the murine prostate adenocarcinoma TRAMP-C2 cell line by CRISPR gene editing. By sequential passaging, we generated a MSH2-KO subclonal population that presents MSI and MMR deficiency, validated by increased tumor mutational burden (TMB) observed by exome sequencing. In studies where we challenged immunodeficient and immunocompetent mice with MMR-proficient (MMRp) and MMRd tumors, the latter showed increase immunogenicity, which led us to interrogate and better characterize such immune responses in the context of immune checkpoint blockade by anti-PD-1.In our studies, MMRd tumor-infiltrating T cells presented significantly enhanced effector and cytotoxic profiles, which likely led to improved tumor control with or without anti-PD-1. We observed an intriguingly lower frequency of SPAS-1 (a well-known TRAMP-C2 immunodominant epitope) antigen-specific T cells in the tumor-reactive fraction of MMRd infiltrates compared to MMRp, which prompted us to interrogate tumor-infiltrate gene expression, TCR repertoire and the potential expansion of multiple antigen-reactive subsets against MMRd tumors in successful immune responses by single cell RNA sequencing and functional ex vivo studies. We also interrogated TCR repertoire data from patients harboring MMRd tumors to add translatability to our findings in mice.Our results constitute a relevant addition to the understanding of immune responses in MMRd tumors and the potential features that could be exploited to improve response rates in immunotherapeutic strategies targeting such malignancies. Citation Format: Marcel Arias Badia, Zenghua Fan, Yee May Lwin, PeiXi Chen, Aahir Srinath, Lawrence Fong. Harnessing immune responses in prostate MMRd tumors treated with immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6420.
Abstract 6015: Methylation synthetic lethality: <i>CHFR</i> methylation and KRAS inhibition in gastric cancers
Authors: Hideyuki Takeshima, Takahiro Ebata, Yumi Furuichi, Satoshi Yamashita, Toshikazu Ushijima
Journal: Cancer Research (2023)

Abstract Synthetic lethality is a promising therapeutic strategy, but the number of founder mutations is limited. In contrast, DNA methylation is frequently present in many types of cancers, and can be a potential target for a synthetic lethality. So far, BRCA1 methylation with a PARP inhibitor is known as a synthetic lethality [Kawachi et al., Breast Cancer Res Treat, 181:323-329, 2020]. In this study, we aimed to identify a novel methylation synthetic lethal combination in gastric cancers. Founder methylation was searched for in 8,008 genes with putative promoter CpG islands (CGIs), and 137 genes which were 1) heavily methylated and 2) frequently methylated in primary gastric cancers (10 or more of 50 cases) were selected. The association analysis between DNA methylation and gene expression showed that 10 of 137 genes were completely silenced in gastric cancer cell lines with methylation of their promoter CGIs, but were expressed in those without. Among these 10 genes, we focused on CHFR, a known tumor-suppressor gene in gastrointestinal cancers, and genes lethal for CHFR methylation were screened for using the sgRNA screening database (The Cancer Dependency Map, DepMap). Comparison of gene dependencies of 17,645 genes between four cell lines with CHFR methylation and 12 cell lines without revealed that knockout of KRAS reduced cell growth specifically in cell lines with methylation. This synthetic lethality could be experimentally confirmed in two cell lines with CHFR methylation, AGS and 44As3, and three cell lines without, HSC41, HSC42, and MKN74. These cell lines included those not used in the screening, validating the usefulness of the combination. These results showed that gastric cancers with CHFR methylation were sensitive to KRAS inhibition, and that methylation synthetic lethality is a promising therapeutic strategy. Citation Format: Hideyuki Takeshima, Takahiro Ebata, Yumi Furuichi, Satoshi Yamashita, Toshikazu Ushijima. Methylation synthetic lethality: CHFR methylation and KRAS inhibition in gastric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6015.
Abstract 6002: Characterizing dynamic landscape of DNA methylation in ovarian high-grade serous carcinoma
Authors: Alexandra Lahtinen, Giovanni Marchi, Daria Afenteva, Susanna Holmström, Kaisa Huhtinen, Anni Virtanen, Johanna Hynninen, Antti Häkkinen, Sampsa Hautaniemi
Journal: Cancer Research (2023)

Abstract Dysregulated DNA methylation (DNAm) is a hallmark of all cancer types, though the precise role of these aberrations in tumor progression and treatment response remains elusive. Advances in whole-genome bisulfite sequencing (WGBS) have enabled profiling methylomes at full resolution and stimulated interest to explore dynamics of DNAm across tumor sites and cancer treatment. A major challenge in the analysis of patient data is that a surgically removed tumor sample represents a mixture of cancer cells and microenvironment, and that the insights on DNAm changes are intertwined due to mixed effects from patient epigenomic background, tissue context, and treatment pressure. By using a computational approach, these effects can be decomposed into patient background, tissue site, and treatment phase specific changes, and controlled for natural microenvironment variation. retion, and action, as well as in several oncogenic signaling cascades. The analysis of the tissue profiles indicated that the progression of HGSC from the tissues-of-origin to the metastatic deposits is accompanied by drastic changes in DNAm profiles. Thus, when comparing ovaries and peritoneum, intra-abdominal tissues mesentery and omentum featured prominent change of promoter DNAm: loss in 10% and gain in 20% of genes. Interestingly, the genes with aberrant DNAm included ABC transporters implicated in pumping drugs across the cell membrane, as well as the members of MAPK and PI3K signaling cascades. The joint analysis of both treatment and tissue contributions suggests that the overall modest effect of NACT is further reduced in metastases, mediated via DNAm changes in genes involved in multidrug resistance. Citation Format: Alexandra Lahtinen, Giovanni Marchi, Daria Afenteva, Susanna Holmström, Kaisa Huhtinen, Anni Virtanen, Johanna Hynninen, Antti Häkkinen, Sampsa Hautaniemi. Characterizing dynamic landscape of DNA methylation in ovarian high-grade serous carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6002.
Abstract 5052: IB-DNQ enhances radiation induced ferroptosis in NQO1-positive cancer cells
Authors: Xiumei Huang, Xiaolin Su, Matthew W. Boudreau, Paul J. Hergenrother
Journal: Cancer Research (2023)

Abstract Cancer is the second leading cause of death worldwide. Current treatments for solid cancers are associated with inherent resistance mechanisms and are ineffective against non-cycling cancer cells. Thus, there is a critical need to develop novel tumor-selective combination therapies to overcome resistance while optimally spare normal tissues. In this study, we investigate the mechanistic basis for tumor-selective potentiation of ionizing radiation (IR) in combination with IB-DNQ, a novel NQO1-bioactivatable agent. We found that combination of a low dose of ionizing radiation (IR, 2 Gy) with a sublethal dose of IB-DNQ dramatically increased Fe2+ leakage and induced elevated lipid peroxidation and ferroptosis in NQO1-positive cancer cells via upregulating the expression of ACSL4, a lipid metabolism enzyme required for ferroptosis. Knockdown of endogenous ACSL4 significantly inhibited lipid peroxidation via downregulating the expression of PTGS2 and dramatically inhibited the cell death that induced by IR or IB-DNQ alone or combination treatment. We further found that this combination treatment significantly decreased IR or IB-DNQ alone mediated upregulation of the expression of GPX4 that led to the accumulation of lipid peroxides, which suggests that IR or IB-DNQ-induced expression of GPX4 may function as a negative feedback loop to restore cell survival upon a sublethal dose of IR or IB-DNQ treatment. Finally, we demonstrated that this combination therapy synergistically suppressed tumor growth and dramatically extended mouse lifespan in orthotopic pancreatic and non-small-cell lung cancer xenograft models. Together, our study provides novel preclinical evidence for new combination therapy in NQO1-positive solid tumors that may overcome IR-induced resistance. Citation Format: Xiumei Huang, Xiaolin Su, Matthew W. Boudreau, Paul J. Hergenrother. IB-DNQ enhances radiation induced ferroptosis in NQO1-positive cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5052.
Abstract 940: Comprehensive characterization of <i>MET</i> exon 14 skipping mutations in non-small cell lung cancer
Authors: Xue Wu, Yaru Zhang, Jiaohui Pang, Li Lin, Jiani C. Yin, Haimeng Tang, Yang Shao
Journal: Cancer Research (2023)

Abstract Background: MET exon 14 skipping mutation (METΔex14) is a key driver event in non-small cell lung cancer (NSCLC), and can be acquired following drug resistance to MET, EGFR or ALK inhibitors. Clinical and genomic features of METΔex14 in NSCLC remain to be further characterized. Methods: A total of 556 baseline samples, 54 MET inhibitor-resistant samples and 16 EGFR/ALK inhibitor-resistant samples from 586 METΔex14 NSCLC patients were included in the analysis. Tissue and/or plasma samples were subjected to targeted next-generation sequencing (NGS) using Geneseeq’s 139/425 cancer-relevant gene panels. Results: The overall frequency of METΔex14 was 1.1%, with a total of 266 distinct variants detected. Of these, 40.2% were base substitutions in the intronic non-coding region immediately adjacent to the splice acceptor site, followed by indels (25.6%) and base substitutions (4.5%) in the splice donor site, and indels (21.4%) and base substitutions (2.3%) in the splice acceptor site, etc. No associations with clinical features were found among different variants. At baseline, METΔex14 commonly co-occurred with TP53 mutations (40.8%), and CDK4 (15.8%) and MET (7.9%) amplifications. In 42 (7.6%) patients, concurrent oncogenic mutations in EGFR, KRAS, ALK, RET, BRAF, and ERBB2 were also detected. Such patients displayed a different spectrum of METΔex14 variants compared with those without concurrent oncogenic mutations (P=0.08). In patients treated with MET inhibitors, no difference in survival was seen among different METΔex14 variants (P=0.38). Notably, activation of EGFR or MET (kinase domain mutations/amplification) conferred primary resistance to savolitinib and crizotinib. In addition, patients with high chromosomal instability or low intratumoral heterogeneity had unfavorable PFS. Secondary resistance to MET-TKI included MET activation (D1228N/H, Y1230C/S, amplification), EGFR activating mutations/amplification, KRAS G12V, as well as FGFR2/4 amplification. Surprisingly, we identified a FGFR3-TACC3 fusion as a previously unreported secondary resistance mechanism to savolitinib in the second line setting. Finally, we found that MET exon 14 skipping mutation might be a rare secondary resistance mechanism to EGFR/ALK inhibitors. Conclusion: In this study, we characterized METΔex14 in a large cohort of NSCLC patients and explored potential primary and secondary resistance mechanisms to savolitinib and crizotinib, which may facilitate drug development and help inform clinical actions. Citation Format: Xue Wu, Yaru Zhang, Jiaohui Pang, Li Lin, Jiani C. Yin, Haimeng Tang, Yang Shao. Comprehensive characterization of MET exon 14 skipping mutations in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 940.
Abstract 4023: Inhitibing GRP78 in non-small cell lung cancer with acquired resistance to EGFR-TKI
Authors: Jaewoo Park, Baskaran Purushothaman, Sera Hong, Munkyung Choi, Joon Myong Song, Keon Wook Kang
Journal: Cancer Research (2023)

Abstract Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have improved the survival of non small cell lung cancer (NSCLC) patients with active mutation of EGFR. However, some of the patients who received EGFR-TKIs showed the acquired resistance, and eventually relapsed within several months. In the TCGA data sets, gene expression of glucose-related protein 78 (GRP78), an ER chaperone, was upregulated in NSCLC tissues. We also confirmed that protein level of GRP78 was increased in HCC827-GR, H1993-GR and H1993-ER NSCLC cell lines with acquired resistance to EGFR-TKIs. Since GRP78 modulates ER stress level which induces ROS and apoptosis, Ru(II) complex 1 and HA15, both the known GRP78 inhibitors induced higher ER stress and ROS generation accompanying more remarkable anti-proliferative and apoptotic effects in EGFR-TKI-resistant NSCLC cell lines. GRP78 level was also found to be higher in H1975, EGFR-TKI-resistant T790M-mutant cell line than other NSCLC cell lines. Blockade of GRP78 also led to apoptosis in H1975, which is consistent with the results found in the acquired EGFR-TKI-resistant cell lines. In summary, we suggest GRP78 targeting as a potential therapeutic strategy for the acquired EGFR-TKI-resistant NSCLC patients. Citation Format: Jaewoo Park, Baskaran Purushothaman, Sera Hong, Munkyung Choi, Joon Myong Song, Keon Wook Kang. Inhitibing GRP78 in non-small cell lung cancer with acquired resistance to EGFR-TKI. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4023.
Abstract 4923: Prostaglandin E2 receptor EP2: A novel target for high-risk neuroblastoma
Authors: Ruida Hou, Ying Yu, Jun Yang, Jianxiong Jiang
Journal: Cancer Research (2023)

Abstract Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. Based on tumor stage and histological features, 50% of NBs are classified as high-risk diseases, a subtype characterized by a quite unsatisfactory long-term survival even with the striking advances in NB management that have been achieved in the past decades. Cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) cascade has been reported to foster a proinflammatory tumor-nourishing microenvironment in NB. However, the specific downstream PGE2 receptor (EP) subtype which directly mediates this tumor promoting effect remains elusive. Therefore, in our research, we aim to 1) elucidate the culprit EP receptor that is directly involved in NB development; 2) evaluate the feasibility of inhibiting the PGE2 receptor subtype as a novel treatment strategy for high-risk NB. To start with, we analyzed the gene expression profiles of the COX2/PGE2/EP pathway from four major NB datasets (Versteeg, Kocak, SEQC, and NRC) on R2 platform. It indicates that the COX-2/PGE2/EP2 signaling axis is highly associated with the expression of high-risk NB markers, as well as an abysmal overall survival rate. Moreover, a time resolved fluorescence resonance energy transfer (TR-FRET) method was adopted to reveal that EP2 receptor is the key Gαs-coupled receptor that mediates PGE2-initiated cAMP signaling in high-risk NB cell lines. Genetic interference of EP2 receptor expression by CRISPR/Cas9-mediated genome editing and doxycycline induced conditional knockdown significantly inhibited high-risk NB development and progression both in neuro-sphere formation assay and in nude mice xenograft models. Finally, we tested the anti-NB efficacy of our recently developed selective and bioavailable small-molecule EP2 antagonists. With a consecutive treatment of three weeks, decreased tumor size and weight have been observed in both high-risk NB xenograft model and immunocompetent allograft model, simultaneously with decreased inflammation, angiogenesis, and enhanced apoptosis. Collectively, our results suggest that the PGE2/EP2 pathway contributes to the growth and malignant potential of high-risk NB; pharmacological inhibition on EP2 receptor by our drug-like compounds might provide a novel therapeutic strategy for this deadly pediatric cancer. Citation Format: Ruida Hou, Ying Yu, Jun Yang, Jianxiong Jiang. Prostaglandin E2 receptor EP2: A novel target for high-risk neuroblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4923.
Abstract 5335: circAde: a circRNA-based system for prolonged and more effective treatment of cancer
Authors: Eoghan T. O'leary, Sara Vikberg, Emilie Foord, Erik D. Wiklund, Lone Ottesen, Victor Levitsky, Thomas B. Hansen
Journal: Cancer Research (2023)

Abstract In recently performed phase I/II clinical studies, we have demonstrated successful delivery of vectorized transgene-encoding mRNA payloads to solids tumors with substantial clinical benefit. In patients, persistent and prolonged transgene expression correlated with positive clinical outcome, and thus temporal expansion of the transgene expression profile is expected to improve the therapeutic benefit even further. Recently, circular RNA (circRNA) has been discovered as a novel class of endogenously expressed RNA. CircRNAs, in contrast to mRNAs, are resistant to exo-nucleolytic decay which results in high intra-cellular stability and persistent expression within cells. Therefore, circRNA-based systems serve as an interesting new technology towards prolonged effects of treatment. Here, we show that our proprietary vector system, circAde, allows high expression of circRNAs through spliceosome-dependent biogenesis. By comparing the protein output from circAde and mRNA-based vectors, we show that the circAde-system out-performs conventional mRNA-based design, both in terms of transgene yield and temporal sustainability of expression. Moreover, using a panel of proof-of-concept-reporters, we show that certain design-features greatly influence the circRNA production and subsequent protein expression from the vector. Without the 5’cap, circRNAs are dependent on IRESs (internal ribosome entry sequences) for effective translation. By conducting two orthogonal IRES screens on 1000+ putative IRES elements, we have identified the most effective IRES sequence in melanoma and lung-cancer cells supporting effective circRNA production and high-yield protein expression, thereby improving our circAde vector system even further. Our results open a new platform towards development of novel, more effective strategies for the treatment of cancer and other settings in which durable transgene expression is desirable. Citation Format: Eoghan T. O'leary, Sara Vikberg, Emilie Foord, Erik D. Wiklund, Lone Ottesen, Victor Levitsky, Thomas B. Hansen. circAde: a circRNA-based system for prolonged and more effective treatment of cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5335.
Abstract 6540: Multiscale protein networks: de novo aberrant protein interactions and oncogenic regulators in seven cancer types
Authors: Won Min Song, Abdulkadir Elmas, Richard Farias, Peng Xu, Xianxiao Zhou, Benjamin Hopkins, Kuan-lin Huang, Bin Zhang
Journal: Cancer Research (2023)

Abstract We conducted integrative proteomic network analyses of 687 cases across 7 cancer types including breast cancer (115 tumor samples), clear cell renal carcinoma (100 tumor samples), colorectal cancer (91 tumor samples), hepatocellular carcinoma (101 tumor samples), lung adenocarcinoma (104 tumor samples), stomach adenocarcinoma (80 tumor samples), and uterine corpus endometrial carcinoma (96 tumor samples). Using Multi-scale embedded gene co-expression network analysis (MEGENA), we constructed co-expression protein network for each cancer type, and interrogated the network topology and co-expressed protein modules. For each cancer type, we identified disease-associated pathways as co-expressed protein modules enriched for differentially expressed proteins in tumor. Comparing with respective cancer transcriptome network models, this systematically revealed proteome-specific cancer subnetworks associated with heme metabolism, DNA repair, spliceosome, oxidative phosphorylation and KRAS oncogenic signaling pahways in several cancer types. Cross-cancer comparison identified highly preserved protein modules showing robust pan-cancer interactions and identified endoplasmic reticulum-associated degradation (ERAD) and N-acetyltransferase activity as the central functional axes. Then, we utilized these network models to predict pan-cancer protein network regulators in the up-stream of disease-associated pathways. The predicted pan-cancer regulators were experimentally validated by loss-of-function to confer anti-tumor effects in diverse cancer types: lung (H847), colon (HCT116), fetal kidney (HEK293T) and breast (MDA-MB-231) cancer cells. Overall, the study was designed to provide tractable network models of cancer proteome, and unlock the further potentials to understand oncogenic regulators and mechanisms in different cancer types. Citation Format: Won Min Song, Abdulkadir Elmas, Richard Farias, Peng Xu, Xianxiao Zhou, Benjamin Hopkins, Kuan-lin Huang, Bin Zhang. Multiscale protein networks: de novo aberrant protein interactions and oncogenic regulators in seven cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6540.